Highly selective coated-electrode nanogap transducers for the detection of redox molecules

ABSTRACT

Highly selective coated-electrode nanogap transducers for the detection of redox molecules are described. In an example, an analyte detection system includes one or more transducer electrodes having a surface for analyte detection. The surface includes a coating to inhibit direct contact of analyte with the surface of the one or more transducer electrodes.

TECHNICAL FIELD

Embodiments of the invention are in the field of devices and methods fordetection of biomolecules such as analytes and, in particular, highlyselective coated-electrode nanogap transducers for the detection ofredox molecules.

BACKGROUND

DNA sequencing is in the throes of an enormous technological shiftmarked by dramatic throughput increases, a precipitously droppingper-base cost of raw sequence, and an accompanying requirement forsubstantial investment in large capital equipment in order to utilizethe technology. Investigations that were, for most, unreachable luxuriesjust a few years ago (individual genome sequencing, metagenomicsstudies, and the sequencing of myriad organisms of interest) are beingincreasingly enabled, at a rapid pace.

Genetic information in living organisms is contained in the form of verylong nucleic acid molecules such as deoxyribonucleic acid (DNA) andribonucleic acid (RNA). Naturally occurring DNA and RNA molecules aretypically composed of chemical building blocks called nucleotides, boundtogether by a phosphate backbone, which are in turn made up of a sugar(deoxyribose or ribose, respectively), and one of four bases, adenine(A), cytosine (C), guanine (G), and thymine (T) or uracil (U). The humangenome, for example, contains approximately three billion nucleotides ofDNA sequence and an estimated 20,000 genes. DNA sequence information canbe used to determine multiple characteristics of an individual as wellas the presence of or susceptibility to many common diseases, such ascancer, cystic fibrosis, and sickle cell anemia. Determination of theentire three billion nucleotide sequence of the human genome hasprovided a foundation for identifying the genetic basis of suchdiseases. A determination of the sequence of the human genome requiredyears to accomplish. Sequencing the genomes or sections of the genome ofindividuals provides an opportunity to personalize medical treatments.The need for nucleic acid sequence information also exists in research,environmental protection, food safety, biodefense, and clinicalapplications, such as for example, pathogen detection, i.e., thedetection of the presence or absence of pathogens or their geneticvariants.

Thus, because DNA sequencing is an important technology for applicationsin bioscience, such as, for example, the analysis of genetic informationcontent for an organism, tools that allow for faster and or morereliable sequence determination are valuable. Applications such as, forexample, population-based biodiversity projects, disease detection,personalized medicine, prediction of effectiveness of drugs, andgenotyping using single-nucleotide polymorphisms, stimulate the need forsimple and robust methods for sequencing short lengths of nucleic acids(such as, for example, those containing 1-20 bases performed withspecific primers. Sequencing methods that provide increased accuracy andor robustness, decreased cost, reduced input sample, and or highthroughput are valuable analytical and biomedical tools.

Additionally, molecular detection platforms that have a reduced capitalcost, are miniaturized and manufacturable in high volumes provide accessto affordable disease detection to many people in places and situationsin which such access was not in the past possible. The availability ofaffordable molecular diagnostic devices reduces the cost of and improvesthe quality of healthcare available to society. Additionally, portablemolecular detection devices have applications in security and hazarddetection and remediation fields and offer the ability to immediatelyrespond appropriately to a perceived security or accidental biologicalor chemical hazard.

However, many improvements are still needed in the area of DNAsequencing and DNA sequencing detection.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates (a) a band diagram at the electrode-redox moleculeinterface in equilibrium without bias, (b) when a bias is applied, (c)potential configuration at oxide coated electrode without bias, (d) wheneV<E_(C)−E_(F)=E₀, and (e) when eV>E_(C)−E_(F)=E₀, in accordance with anembodiment of the present invention.

FIG. 2 is a plot showing a comparison of band energy levels of potentialprotective dielectric films and their position with respect to theplatinum work function, which defines the energy barrier.

FIG. 3 is a cross-sectional scanning electron micrograph of a nanogapdevice showing 3 nm thick TiO₂ coating layers on platinum electrodes, inaccordance with an embodiment of the present invention.

FIG. 4 illustrates cross-sectional views representing various operationsin a method of fabricating a nanogap transducer device with protectivecoatings, in accordance with an embodiment of the present invention.

FIG. 5 depicts several cyclic voltammetry plots for a Pt-Pt nanogapdevice with 3 nm TiO₂ coatings using a model compound (10 uM Ferroscene)of redox potential at about 0.240V, in accordance with an embodiment ofthe present invention.

FIG. 6 illustrates examples of organic molecules suitable for electrodecoating, in accordance with an embodiment of the present invention.

FIG. 7 is a plot demonstrating UV-Vis monitoring of a redox activemolecule aminophenol on coated electrode compared with bare electrode,in accordance with an embodiment of the present invention.

FIG. 8 illustrates alendronate derivatives suitable for organiccoatings, in accordance with an embodiment of the present invention.

FIG. 9 illustrates a schematic of a nanogap transducer device withprotective coatings, in accordance with an embodiment of the presentinvention.

FIG. 10 illustrates an organic coated metal electrode surface along withsuitable molecular coatings, in accordance with an embodiment of thepresent invention.

FIG. 11 includes a plurality of CV scans of coated nanogap devices, inaccordance with embodiments of the present invention.

FIG. 12 is a plot demonstrating the effects of a DTT4 coating on a Ptnanogap, in accordance with an embodiment of the present invention.

FIG. 13 illustrates a computing device in accordance with oneimplementation of the invention.

FIG. 14 illustrates a block diagram of an exemplary computer system, inaccordance with an embodiment of the present invention.

DESCRIPTION OF THE EMBODIMENTS

Highly selective coated-electrode nanogap transducers for the detectionof redox molecules are described. In the following description, numerousspecific details are set forth, such as detection approaches, in orderto provide a thorough understanding of embodiments of the presentinvention. It will be apparent to one skilled in the art thatembodiments of the present invention may be practiced without thesespecific details. In other instances, well-known features, such asintegrated circuit design layouts, are not described in detail in orderto not unnecessarily obscure embodiments of the present invention.Furthermore, it is to be understood that the various embodiments shownin the Figures are illustrative representations and are not necessarilydrawn to scale.

One or more embodiments are targeted to DNA sequencing using electricaldetection technology. Embodiments may address approaches for providing acompact DNA sequencing platform suitable to perform highly sensitivesignal detection in a highly parallel fashion. Furthermore, one or moreembodiments provide a cost effective and accurate sequencing system toenable wide applications of genomic information for the improvement ofhuman health. To provide context, conventional DNA sequencing technologycan be used to decode an individual's genomic DNA sequence of over 3billion base pairs. However, the total cost of DNA sequencing remainsprohibitive at least in part due to complex instrumentation and costlyconsumables. For routine biomedical analyses, a DNA sequencing platformneeds to be compact, sensitive, accurate and exhibit high throughputsuch that the overall cost is affordable.

The ability to detect biomolecules at ultra-low concentrations has thepotential to revolutionize several fields including diseasedetection/treatment and environmental screening/monitoring.Manufacturing electronic biochemical sensors with high sensitivity andthe potential for massively parallel scaling will allow the realizationof highly affordable, customizable, and miniaturized systems for suchapplications including DNA sequencing platforms, in accordance with anembodiment of the present invention.

One or more embodiments described herein are directed to the design andmanufacturing of a high sensitivity sensor which can detect reactionproduct(s) from biochemical reactions involving single molecules usingredox cycling-based detection. Such embodiments may be implemented tosignificantly improve the signal to noise ratio in a transduction schemeused in DNA sequencing platforms for signal transduction, which involvesdetection of a redox-active molecule using redox cycling in nanogaptransducers. As such, improved sensitivity in detection of DNA may beachieved, pushing towards single-molecule detection.

To provide further context, it is to be appreciated that a number ofproblems may be associated with existing redox cycling transducers,which utilize platinum as an electrode material. First, a resultingcatalytic effect of metal on redox tag degradation can lower signallevel. Second, high background current can mask the actual signal to bedetected (i.e., providing high noise). Third, adsorption of detectedspecies on electrodes can result in lowering the total signal level(i.e., resulting in low signal). Fourth, the operation potential may belimited depending on the electrode properties interacting with thebackground (e.g., limited redox species that can be used as a tag,minimizing the optimization window and ultimately decreasing the optimalsignal level). Noble metals (e.g., Pt, Au, Ag) are typically used aselectrodes for redox measurements because of their chemical stability.However, their chemical catalytic properties can also be adverse tomeasurement sensitivity and accuracy because organic analytes and watermolecules that are in direct contact with the metal atoms can undergomolecular conversion or electrolysis more easily. Such a catalyticeffect may result in high background current and analyte degradation.One or more embodiments described herein provide solutions to reduce theabove described catalytic effect.

Past approaches to addressing the above issues have partially reducedthese problems by using diamond, which possesses better electrochemicalproperties. However, diamond is usually deposited at high temperaturesthat are not CMOS-compatible. In a first aspect, in accordance with anembodiment of the present invention, a transducer electrode material(e.g., platinum or any other electrochemically active material such asdiamond, gold, ITO, Iridium oxide, etc) is coated with a very thin(e.g., between 0 to 7 nm thick) dielectric film (e.g., Ta₂O₅, TiO₂,SiO₂, Y₂O₃, Al₂O₃, HfO₂, ZrO₂, ZrSiO₄, BaTiO₃, BaZrO₃, Si₃N₄, etc.), toprevent or reduce any catalytic reaction of the transducer material withsolution additives. Furthermore, such coating may be performed to reduceadsorption, without significantly affecting the electron transfer at thereducing and oxidizing electrodes. In one embodiment, the dielectricfilm coating possesses a low energy barrier (see FIGS. 1 and 2) toenable electron tunneling or hopping through or over the energy barrierto maintain a similar electron transfer rate as compared with bareelectrodes. In another embodiment, thin conductive materials that arenon-catalytic and non-electrochemically/electrochemically active canalso be used as protective films on electrochemically active films or ona combination of electrochemically active films.

In an embodiment, a method for reliably fabricating a redox cyclingsensor in a CMOS compatible manner is provided, allowing denseintegration on a single platform. Such a redox cycling sensor can be asdescribed in US patent publication 2011/0155586 filed Dec. 31, 2009 andentitled, “Nanogap chemical and biochemical sensors,” which isincorporated by reference herein. Embodiments described herein mayinclude similar or the same devices but may have the added feature ofdepositing a very thin (e.g., between approximately 0 to approximately 7nm thick) dielectric film on both the bottom and top electrode material.Such devices may be used to maximize a signal to noise ratio for thedetection of any molecule that can go through reversible (or quasireversible, since depending on the detection scheme short lifetimereactions can also be detected) redox reactions. In an embodiment, thesame or similar coating scheme can also be used on transducers thatpossess one working electrode whereby cycling is accomplished chemicallyinstead of electrically, as is the case for the nanogap transducerscheme.

To provide further context, in the case of DNA sequencing, a biochemicalassay system (reaction) has been designed so that nucleotide basespecific redox tags are activated between two electrodes separated by ananogap (e.g., a gap of 50 nm or less). A third reference electrode maybe used to fix the bias of the fluid. The presence of the active redoxtags are detected by monitoring either one of the two electrodecurrents. Having two closely spaced electrodes biased close to thereduction and oxidation potentials of the redox tag allows signalamplification because the same molecule carries electrons from theoxidation electrode to the reduction electrode through the gap betweenthese electrodes multiple times. Placing the electrodes closer to eachother results in higher signal because it decreases the diffusion timeof the redox tag from one electrode to another. The amount of currentregistered is proportional to the number of non-adsorbed molecules inthe gap. In accordance with an embodiment of the present invention,coating the electrode material with a thin dielectric film in such ananogap redox cycling architecture provides for higher signal to noiseratio. Such an implementation can allow the readout circuitry todiscriminate the redox current due to the redox tag with minimumbackground current contribution from the buffer. Furthermore, thematerial architecture can present an inert surface, minimizingadsorption of molecules so more of the molecules can keep shuttling moreelectrons resulting in more signal. Thus, embodiments described hereincan be based on an understanding of tunneling and hopping theoriesbehind electron transfer at the dielectric redox molecule interface, andmethods to fabricate nanogap devices with such coatings are thusoutlined. Designs described herein may utilize a minimum number offabrication operations, decreasing the manufacturing cost and improvingthe yield.

As a comparison, state-of-the art nanogap sensor electrodes arefabricated to have bare electrochemically-active electrodes (e.g.,conductive materials such as platinum, diamond, gold, ITO, iridiumoxide, etc.). With such electrodes, problems outlined above have beenaddressed by one or more of the following: (1) operating the device atelectrode potentials in which the background is minimal, (2) usingelectrode surface modifications to minimize adsorption on surfaces, (3)using optimized electrolyte or buffer conditions to minimize adsorptionon surfaces, (4) using increased concentrations of analyte to get moresignal from the devices, (5) alternatively, if the analyte tends topolymerize on the surface, using reduced concentrations of analyte toreduce the rate of electrode fouling, or (6) choosing redox compoundsthat are within the operational range of the devices defined by thepotential scanning window of the used electrode materials. However, suchprocedures have proven very complex, time consuming and do notnecessarily produce repeatable results, thereby reducing reliability andrepeatability.

Thus, as touched on above, in a first aspect, embodiments are directedto coating, and thus protecting, transducer electrode material (e.g.,platinum or any other electrochemically active material such as diamond,gold, ITO, iridium oxide, etc.) with a very thin (e.g., approximately inthe range of 0 to 7 nm thick) dielectric film (e.g., Ta₂O₅, TiO₂, SiO₂,Y₂O₃, Al₂O₃, HfO₂, ZrO₂, ZrSiO₄, BaTiO₃, BaZrO₃, Si₃N₄, etc), to reduceor altogether prevent catalytic reaction of the transducer material withsolution additives and to reduce the effect of adsorbed species, withoutsignificantly affecting the electron transfer at the reducing andoxidizing electrodes. As mentioned above, the dielectric film shouldpossess a low energy barrier to enable electron tunneling or hoppingthrough or over the energy barrier to maintain a similar electrontransfer rate as with bare electrodes. Thin conductive materials (e.g.,Ru) that are non-catalytic and non-electrochemically active can also beused as protective films. By doing so, in an embodiment, the abovestate-of-the art solutions need not be implemented thereby reducingcomplexity, increasing yield and producing reliable and repeatableresults. Moreover, embodiments described herein allow for the option tooperate at a wider range of electrode potentials, increasing the optionsfor redox tags. Increasing redox tag options allows for the optimizationof the tag molecules for maximum signal. In addition, the developedprocess is scalable such that semiconductor manufacturing scalabilitycan be exploited to reduce the size of the sensor. Finally, the same orsimilar coating scheme can also be used on transducers that possess oneelectrode (excluding a reference electrode) whereby cycling isaccomplished chemically instead of electrically as it is the case forthe nanogap transducer scheme.

Thus, embodiments described herein can provide a scalable andintegratable manufacturing process for producing redox sensors.Moreover, development of the theory behind previous solutions describedabove has provided the opportunity to tune the parameters that canprovide the best sensitivity. In particular, allowing the selection ofoptimal electrode coatings. In one or more embodiments of the presentinvention, as described below, theory along with a combination ofstate-of-the art devices integrated with new materials and processingoperations enables the use of, and benefit of, electrode coatingmaterials.

FIG. 1 illustrates (a) a band diagram at the electrode-redox moleculeinterface in equilibrium, (b) when a bias is applied, (c) potentialconfiguration at oxide coated electrode without bias, (d) wheneV<E_(C)−E_(F)=E₀, and (e) when eV>E_(C)−E_(F)=E₀, in accordance with anembodiment of the present invention.

Referring to part (a) of FIG. 1, as shown schematically, underequilibrium conditions (i.e., no applied bias), the effective electronicdensities of states of the reduced and oxidized ionic species in contactwith the electrode surface are provided. The effective electronicdensities of states are most properly considered as the relativeprobability, in a redox process, of adding an electron of a given energyto the oxidized species or removing an electron of a given energy fromthe reduced species. Near the Fermi level, an exponential approximationis often considered. When a bias V (part (b) of FIG. 1) is applied, itleads to a net electronic current from the reduced species to theelectrode (or from the oxidized species to the electrode). In anembodiment, the electrodes are coated with a thin dielectric throughwhich the electron tunnels or hops over an effective energy barrier(part (c) of FIG. 1).

In the case that eV<E_(C)−E_(F)=E₀ (part (d) of FIG. 1), the currentassociated with the electron transfer rate through tunneling is given byequation (1):

$\begin{matrix}{{I(V)} = {\int_{0}^{{- E_{F}} + V}\frac{{{qy}(E)}{\exp\begin{pmatrix}\left( {{- 2^{E/2}}D{\sqrt{m}/h}} \right) \\\left( {{E_{o +}\frac{1}{2}{qV}} + E_{F} - E} \right)^{\frac{1}{2}}\end{pmatrix}}{{DOS}\left( {E - {qV}} \right)}{\mathbb{d}E}}{{\exp\left( {\left( {E_{F} - E} \right)/{kT}} \right)} + 1}}} & (1)\end{matrix}$

In the case that eV>E_(C)−E_(F) (part (e) of FIG. 1), the currentconsists of two contributions: electrons with energy less and greaterthan E_(V)−E₀. The current generated from electrons with energy lessthan E_(V)-E₀ is the same as equation (1), whereas the current generatedfrom electrons with energy greater than E_(V)-E₀ is given by equation(2):

$\begin{matrix}{{I(V)} = {{\int_{0}^{{- E_{F}} + E_{0}}\frac{{{qy}(E)}{\exp\begin{pmatrix}\left( {- \frac{2^{\frac{3}{2}}D\sqrt{m}}{h}} \right) \\\left( {{E_{0 +}\frac{1}{2}{qV}} + E_{F} - E} \right)^{\frac{1}{2}}\end{pmatrix}}{{DOS}\left( {E - {qV}} \right)}{\mathbb{d}E}}{{\exp\left( \frac{\left( {E_{F} - B} \right)}{kT} \right)} + 1}} + {\int_{{- E_{F}} + E_{0}}^{{- E_{F}} + {qV}_{0}}\frac{{{qy}(E)}{\exp\left( {\left( \frac{2^{\frac{3}{2}}D\sqrt{m}}{h} \right)\left( {{E_{u +}{qVE}_{F}} - E} \right)^{\frac{1}{2}}} \right)}{{DOS}\left( {E - {qV}} \right)}{\mathbb{d}E}}{{\sqrt{2}{qV}\;{\exp\left( \frac{\left( {E_{F} - E} \right)}{kT} \right)}} + 1}}}} & (2)\end{matrix}$

Ideally, operation should be in the eV>E_(C)-E_(F) case to maximize theelectron transfer rate while reducing the applied bias V. To do so,however, in an embodiment, dielectrics with low energy barriers areused. Thinner films should also be deposited to reduce the tunnelingdistance but a compromise needs to be struck between film thicknessesand reduced electrode-catalytic activity and fouling.

FIG. 2 is a plot 200 showing a comparison of energy band levels ofpotential protective dielectric films and their position with respect toplatinum work function, which defines the energy barrier. Referring toFIG. 2, various dielectric films are demonstrated as compared to aplatinum electrode. It is to be appreciated that the list of 11dielectric films in plot 200 is not restrictive and may be extended toany other dielectric material. The same is applied to electrode materialthat can be any electrochemically active material. Moreover, thinconductive materials that are non-catalytic and non-electrochemicallyactive can also be used as protective films. Finally, it is to beappreciated that operating at higher temperatures can spread theelectronic density of states, and increase the electron energy whichwill in turn increase the electron tunneling and hopping probabilities,thereby increasing the electron transfer rate.

In accordance with an embodiment of the present invention, a newfabrication process is described for incorporating a protectivedielectric film (or conductive film that is non-catalytic andnon-electrochemically active), such as those described above, whichconsists of depositing a thin (e.g., between approximately 0-7 nm thick)film using atomic layer deposition (or any other deposition proceduresuch as sputtering, evaporation, etc). The resulting fabricatedtransducer may be utilized for DNA sequencing. The resulting transducermay also be utilized for enzymatically tagged assays. More generally,one or more embodiments described herein provide a unique combination ofusing protective coatings on electrodes with a nanogap architecture forredox cycling detection of molecules.

FIG. 3 is a cross-sectional scanning electron micrograph 300 of ananogap device showing 3 nm thick TiO₂ coating layers on platinumelectrodes, in accordance with an embodiment of the present invention.Referring to FIG. 3, a sacrificial layer, which can selectively beetched such as chromium, tungsten, etc., was etched to provide aapproximately 50 nm gap 302 between the electrodes.

FIG. 4 illustrates cross-sectional views representing various operationsin a method of fabricating a nanogap transducer device with protectivecoatings, in accordance with an embodiment of the present invention.

Referring to part (a) of FIG. 4, a bottom electrode 402 is formed on orabove a substrate 400. In one embodiment, the bottom electrode 402 isfabricated via a material deposition, lithography, hardmask deposition,and etching processing scheme. In one embodiment, the bottom electrode402 is formed to have minimal surface roughness and with minimalthickness in order to minimize the probability of later shorting of thetop and bottom electrodes. Roughness may cause openings in thesacrificial conformal coating and edges with high aspect ratios maycause thinning/voids in the sacrificial layer. In one embodiment, thebottom electrode 402 is composed of a material such as, but not limitedto, platinum, gold, diamond, ITO or iridium oxide, and is deposited witha technique such as, but not limited to, evaporation, sputtering, ALD,CVD or hot filament. In the case of diamond, a thick film may need to bedeposited and high aspect ratio structures at the edges of theelectrodes may be formed. Such high aspect ratio structures may lead tothinning of the sacrificial film at the edges of the electrodes,increasing the probability of shorting between the top and bottomelectrodes. To mitigate such issues, in one embodiment, the nanogapdevices may be planarized by depositing a dielectric layer (e.g.,silicon nitride or silicon dioxide) and using chemical mechanicalpolishing (CMP) of the dielectric to achieve a planar surface forsubsequent enhanced conformal coating of the following layers. In someembodiments, an adhesion layer such as chromium, tantalum, or variousother adhesion layers may be utilized to improve bonding between theelectrode and the substrate.

Referring to part (b) of FIG. 4, a protective film 406 is then formed onthe structure of part (a) of FIG. 4. In one embodiment, the protectivefilm 406 is formed by deposition and patterning of the material layer ofthe protective film 406. In one embodiment, subsequent to deposition ofthe protective film material, the combination of the bottom electrodeand the protective film can be defined via lift-off or etchingprocedures. In the case that the protective film is a dielectric, thebottom electrode can be patterned and then the dielectric protectivefilm can subsequently be deposited without any further patterning.

Referring to part (c) of FIG. 4, a sacrificial layer 408 is formed onthe structure of part (b) of FIG. 4. In one embodiment, the sacrificiallayer 408 is formed by a deposition and patterning approach. In oneembodiment, the sacrificial layer 408 is composed of a material such as,but not limited to, Cr, W or Ti and has a thickness of approximately 100nm or less. In one embodiment, the sacrificial layer 408 is formed by adeposition technique such as, but not limited to, sputtering,evaporation or ALD, and is patterned by lift-off or etching (wet or dry)techniques. In a specific embodiment, the ALD approach enables highlyconformal coatings with high degree of thickness control, enabling verythin (e.g., less than 100 Angstroms) nanogaps which can further improvedevice sensitivity and minimize thinning/opening on potentially highaspect ratio electrode structures to provide devices with higherreliability (fabrication yield).

Referring to part (d) of FIG. 4, a top electrode 410 and correspondingprotection layer 412 are formed on the structure of part (c) of FIG. 4.In one embodiment, the protective layer 412 is deposited first is amanner similar to formation of protection layer 406. The top electrode410 material is then deposited and the combination of top electrode andprotective layer can be patterned via lift-off or etching (dry/wet)techniques. In the case of the protective film being a dielectric, theprotective film 412 does not need to be patterned, although it is shownas patterned in FIG. 4.

Referring to part (e) of FIG. 4, a passivation layer 414 is formed onthe structure of part (d) of FIG. 4. In one embodiment, after thedeposition and patterning of the top electrode (e.g., patterning isperformed to leave an opening to access the sacrificial layer and thegap), a passivation dielectric 414 is deposited to minimize backgroundcurrent during measurement. In an exemplary embodiment, the passivationlayer 414 is a layer of Plasma enhanced chemical vapor deposition(PECVD) Nitride/Oxide/Nitride (2300 A/3000 A/2300 A). Other dielectriclayers such as SiC(O/N) or polymer layers such as polyimide can be usedas a passivation layer given that the process is optimized to ensure thelong term reliability/stability of the passivation layer and minimalleakage of current in the buffer fluid. Referring to part (f) of FIG. 4,the sacrificial layer 408 is then etched away using an appropriateselective wet etch to generate the nanogap geometry.

It is to be appreciated that other process fabrication schemes can alsobe pursued such as the deposition of a stack making up the layers all atonce (e.g., bottom electrode/protective coating/sacrificiallayer/protective coating/top electrode) and patterned via lift-off oretching (e.g., dry/wet) followed by subsequent top electrode contactdefinition and passivation. Although devices presented herein were, inaccordance with one embodiment, fabricated using plain siliconsubstrates, the process can be repeated on planarized CMOS wafers formonolithic integration of the transducers with electronics.

FIG. 5 is a plot 500 of cyclic voltammetry plots for a Pt-Pt nanogapdevice with 3 nm TiO₂ coatings using a model compound (10 uM Ferrocene)with a redox potential at about 0.240V, in accordance with an embodimentof the present invention. Referring to FIG. 5, cyclic voltammetry plotsobtained with nanogap devices made of Pt electrodes and protected usingTiO₂ films deposited using ALD reveal the superior electrochemicalproperties of such devices due to the reduced fouling effect.

In a second aspect, in accordance with another embodiment of the presentinvention, organic surface modified, i.e., coated, electrode nanogaptransducers suitable for redox-based biochemical chemical sensing aredescribed. One or more embodiments are directed to electrode surfacemodification processes and chemistry approaches additional to (i.e., inplace of or in combination with) the above described protective filmcoated electrode nanogap transducers for the detection of redoxmolecules.

To provide context, sensitivity and specificity to detect biomoleculesand chemicals at ultra-low concentrations has the potential torevolutionize several fields including clinical diagnostics, epidemicdisease control, environmental monitoring, and food safety.Manufacturing electronic biomolecule and chemical sensors withscalability and speed enables the realization of highly affordable,customizable, and miniaturized systems for such applications includingstate-of-the-art DNA sequencing platforms.

One or more embodiments are directed to coating a transducer electrodematerial (e.g., platinum or other electrochemically active material suchas diamond, gold, ITO, iridium oxide, etc.) with a well-defined orself-assembled monolayer or with very thin multiple layers ofhydrophilic and biocompatible organic compounds (e.g.: polyethyleneglycols, anilines, phosphonates, thiols, peptides, etc.), to reduce orprevent entirely catalytic reaction of the transducer material with thesolution and or solution additives and reduce adsorption of the redoxtags, without significantly reducing the electron transfer at thereducing and oxidizing electrodes. In one such embodiment, the organicor biomolecular coating possesses a low energy barrier to enableelectron tunneling or hopping through or over the energy barrier tomaintain a similar (e.g., 90 to 100%) electron transfer rate as withbare electrodes. In a specific embodiment, the coating is non-catalyticand non-electrochemically active (or with reduced catalytic andelectrochemical activity) and can also be used as a protective film toreduce fouling or denaturing during analysis.

To provide context, the microstructure, cleanliness and chemicalcomposition of an electrode surface in part determines how anelectron-transfer reaction proceeds. Embodiments described hereininclude a method to protect an electrode surface from contamination bycoating. The contact angle of a water droplet against a surface is ameasure of the surface hydrophilicity. Experiments performed on cleanplatinum and gold have both demonstrated a hydrophilic nature. However,within only minutes of exposure to ambient laboratory conditions, bothsurfaces become increasingly hydrophobic. This change is attributed toadsorption or nonspecific binding of various chemical species to themetal surfaces, indicating surface contamination.

One or more embodiments are directed to approaches for reliablyfabricating a redox cycling sensor in a CMOS compatible manner, allowingdense integration on a single platform. The resulting devices may be, inan embodiment, similar to existing nanogap devices with the addedfeature of a coating of a well-defined or self-assembled monolayer orvery thin multiple layers of hydrophilic and biocompatible organiccompounds on both the bottom and top electrode material. The coating canbe utilized to maximize the signal to noise ratio and to reduce foulingfrom occurring for the detection of any molecule that can go throughreversible (or quasi reversible: depending on the detection scheme shortlifetime reactions can also be detected) redox reactions. The same orsimilar coating scheme can also be used for transducers that possess oneelectrode (excluding a reference electrode if used) whereby cycling isaccomplished chemically instead of electrically, as in the case of ananogap transducer scheme.

In accordance with an embodiment of the present invention, in the caseof DNA sequencing, a biochemical assay system (reaction) has beendesigned so that redox tags, that can be base specific, are generatedclose to or between two electrodes separated by a nanogap (e.g., 100 nmor less). A third reference electrode may be used to fix the bias of thefluid. The presence of the redox tags are detected by monitoring eitherone of the two or both electrode currents. Monitoring both electrodespermits detection of anti-correlated currents associated with the twoelectrodes when very small numbers of redox tags are present in thenanogap. Having two closely spaced electrodes biased close to thereduction and oxidation potentials of the redox tag allows signalamplification because the same molecule carries electrons from theoxidation electrode to the reduction electrode through the gap betweenthese electrodes multiple times. Placing the electrodes closer to oneanother can result in higher signal since the increased proximitydecreases the diffusion time of the redox tag from one electrode toanother. The amount of current registered is proportional to the numberof non-adsorbed molecules in the gap. In an embodiment, coating theelectrode material with a well-defined or self-assembled monolayer orwith very thin multiple layers of hydrophilic and biocompatible organiccompounds in such a nanogap redox cycling architecture enablesachievement of higher signal to noise ratio and prevents the occurrenceof fouling. In a specific embodiment, the result allows correspondingreadout circuitry to discriminate the redox current due to the redoxlabel with minimum background current contribution from the buffer. Theoutcome may also be to present an inert surface, minimizing adsorptionof molecules such that the same molecule can shuttle more electronsresulting in more signal. The design uses a minimum number offabrication steps, decreasing the manufacturing cost and improving theyield.

One or more embodiments involve coating and thus protecting thetransducer electrode material (e.g., platinum or anotherelectrochemically active material such as diamond, gold, ITO, iridiumoxide, etc) with a well-defined or self-assembled monolayer or with verythin multiple layers of hydrophilic organic polymer or biopolymers. Inone embodiment, the coating is suitable to prevent (or at leastsubstantially inhibit) catalytic reaction of the transducer materialwith solution additives and reduce the effect of adsorbed species,without affecting the electron transfer at the reducing and oxidizingelectrodes. The coating layers can also be controlled with certaincharge density to enhance electron transfer rate compared to bareelectrodes. In one embodiment, the coatings are non-catalytic andnon-electrochemically active (or with reduced catalytic andelectrochemical activity) and can also be used as protective films toreduce fouling and denaturing. By changing the coating structure andcharge properties, the electron transfer can be enhanced to improve thesensitivity. By doing so, previous solutions may not be needed, reducingcomplexity, increasing yield and producing reliable and repeatableresults. Moreover, embodiments described herein can provide the optionto operate at a wider variety of electrode potentials, increasing theoptions for redox tags that allows for the optimization of the tagmolecules for maximum signal. In addition, the developed process may bescalable such that semiconductor manufacturing scalability may be usedto reduce the size of the sensor.

FIG. 6 illustrates examples of organic molecules suitable for electrodecoating, in accordance with an embodiment of the present invention.Referring to part (a) of FIG. 6, tetra-DTT phosphates may be used as asurface coating molecule. Referring to part (b) of FIG. 6,tetra-DTT-ferrocene phosphates may be used as a surface coatingmolecule. These examples may be included on an electrode surface by afabrication process suitable to incorporate the protective organiccoating, such as processes described herein. Applications include usageof a resulting transducer for DNA sequencing or for enzymatically taggedassays.

In an embodiment, a unique combination of incorporating protectiveorganic coatings on electrodes with a nanogap architecture for redoxcycling detection of molecules is achieved. The fabrication process flowmay be viewed as having five main considerations (and variationsthereof) which are outlined below.

In a first consideration, in an embodiment, formation of the bottomelectrode involves formation of the bottom electrode (e.g., as adeposited material) with minimum surface roughness and with minimumthickness in order to minimize the probability of shorting of the topand bottom electrodes. Roughness may cause openings in a correspondingsacrificial conformal coating and the edges with high aspect ratios maycause thinning or voids in the sacrificial layer. In one suchembodiment, the bottom electrode (e.g., platinum, gold, diamond, ITO,iridium oxide, etc.) is deposited with a suitable technique (e.g.,evaporation, sputtering, ALD, CVD, hot filament, etc.). In the case thatthick films are required for deposition (e.g. diamond), high aspectratio structures at the edges of the electrodes are created. The highaspect ratio structures can cause thinning of the sacrificial film atthe edges of the electrodes, increasing the probability of shortingbetween the top and bottom electrodes. To mitigate this problem, in oneembodiment, the nanogap devices are planarized by depositing adielectric layer (e.g., silicon nitride or silicon dioxide) and usingchemical mechanical polishing (CMP) of the dielectric to achieve aplanar surface for enhanced conformal coating of the following layers.

In a second consideration, regarding formation of the sacrificial film,in an embodiment, a sacrificial layer (e.g., Cr, W, Ti, etc) that isapproximately 500 Angstroms in thickness or less, is deposited (bysputtering, evaporation, ALD, etc.) and patterned by lift-off or anetching (wet or dry) approach. The ALD technique can enable highlyconformal coatings with a high degree of thickness control, enablingvery thin (e.g., less than approximately 100 Angstroms) nanogaps whichwill further improve device sensitivity and minimal thinning/opening onpotentially high aspect ratio electrode structures to provide deviceswith higher reliability.

In a third consideration, regarding formation of the top electrode, inan embodiment, the top electrode material is deposited and thecombination of top electrode and protective layer is patterned vialift-off or etching (dry/wet) techniques.

In a fourth consideration, regarding passivation of the nanogap devices,in an embodiment, subsequent to deposition and patterning of the topelectrode (e.g., patterning is performed to leave an opening to accessthe sacrificial layer and the gap), a passivation dielectric isdeposited to minimize background current during measurement. In anexemplary embodiment, a layer of plasma enhanced chemical vapordeposition (PECVD) Nitride/Oxide/Nitride (2300 A/3000 A/2300 A) is usedas a passivation layer. Other dielectric layers such as SiC(O/N) orpolymer layers such as polyimide can be used as a passivation layergiven that the process is optimized to ensure the long termreliability/stability of the passivation layer and minimal leakage ofcurrent in the buffer fluid. The sacrificial layer may then be etchedaway in the appropriate selective wet bath to create the nanogapgeometry.

In a fifth consideration, regarding surface coating, in an embodiment,other processes can also be implemented such as the deposition of astack making up the layers all at once (e.g., bottomelectrode/protective coating/sacrificial layer/protective coating/topelectrode) and patterned via lift-off or etching (dry/wet) followed bysubsequent top electrode contact definition and passivation.

In an embodiment, applying the organic material coating is performed byphysical absorption, chemical bonding and/or by electroplating. Althoughdevices presented herein may be contemplated as fabricated using plainsilicon substrates, the process can also be implemented on planarizedCMOS wafers for monolithic integration of the transducers withelectronics.

FIG. 7 is a plot 700 demonstrating UV-Vis monitoring of a redox activemolecule aminophenol on coated electrode compared with bare electrode,in accordance with an embodiment of the present invention. Referring toplot 700, the red-shifting from 238 nm to 260 nm and from 300 nm to 370nm indicates the catalytical oxidation of aminophenol. The organiccoating minimized the catalytical activity of the electrode Pt surface.Among the coatings (e.g., aniline, aza-adenine, poly-adenosine (polyA),mercaptoundecanol (Thiol-C11OH), and polyethylene glycol (PEG)), theaniline rendered most effective protection, in a particular embodiment.

FIG. 8 illustrates alendronate derivatives suitable for organiccoatings, in accordance with an embodiment of the present invention.Referring to FIG. 8, exemplary structures are shown for positivederivatives 802, neutral derivatives 804, negative derivatives 806, andmediating derivatives 808.

FIG. 9 illustrates a schematic of a nanogap transducer device 900 withprotective coatings, in accordance with an embodiment of the presentinvention. Referring to FIG. 9, solid electrodes are shown asorganic-coated nanogap electrodes 902 and 904. In one embodiment, theorganic coating is applies subsequent to electrode fabrication, asdepicted.

FIG. 10 illustrates an organic coated metal electrode surface along withsuitable molecular coatings, in accordance with an embodiment of thepresent invention. Referring to FIG. 10, a noble metal electrode 1002has thereon a thiol compound-based surface coating 1004. The grouping ofexemplary molecules 1006 provide additional examples of suitable surfacecoating molecules.

FIG. 11 includes a plurality of CV scans 1100 of coated nanogap devices,in accordance with an embodiment of the present invention. Referring toFIG. 11, alendronate and derivatives coating over TiO₂ on Pt nanogaps isdemonstrated where each graph of 1100 is overlaid 10 uM pAP data fromfour devices. Additionally, FIG. 12 is a plot 1200 demonstrating theDTT4 coating effect on a Pt nanogap, in accordance with an embodiment ofthe present invention.

For all aspects described above, in an embodiment, the resulting devicescan be utilized for fabricating an ultra dense array of chemicallymodified sensors on a silicon platform for whole genome sequencing. Inone such embodiment, each sensor is used to detect the chemical signalgenerated (e.g., in the form of a redox active molecule) from thetest/fill reaction at a specific location, identifying the base pair.These devices may be crucial in sensing signaling molecules beingproduced at each location. However the above described usage is not solimited. For example, in another embodiment, electrodes having coatingsas described above provide an enabling technology for the denselyintegrated transducer array through sensitive and robust detection ofbase specific redox tags. Improving the signal to noise ratio of thetransducers allows the detection with higher confidence and also relaxesthe requirements on the associated biochemistry. In general, embodimentsdescribed herein may be suitable for a variety of implementationsinvolving high sensitivity electronic biosensor array-basedapplications. Applications can range from having the redox activespecies as analytes in a solution or using the redox active molecule asa label for the detection of some primary specie as done in our case.Some examples of applications in which redox actives species may play arole can be in high throughput DNA sequencing, biomolecule detection fordisease monitoring, point of care diagnostics.

To provide another general context, overall, one or more embodiments aredirected to performing redox detection, such as DNA sequencing, based onelectrical signal detection. An integrated electronic circuit can beused to detect such signals. The combination of the chemistry schemewith CMOS integrated circuits (ICs) and sequencing applications providesadvantages not previously realized in conventional detection approaches.Furthermore, CMOS IC chips can be used for massive human genome sequenceinformation generation, which can leverage advanced fabricationtechnology.

As used herein, “sensor” or “transducer” refers to a substance or devicethat detects or senses an electrical signal created by movement ofelectrons, including but not limited to electrical resistance, current,voltage and capacitance. That is, the transducer or sensor can detectsignals in the form of current, or detect voltage, or detect charge, orimpedance or magnetic field, or a combination thereof. A transducerarray has one or more transducers, up to billions of transducers.

An “array” is an intentionally created collection of substances, such asmolecules, openings, microcoils, detectors and/or sensors (ortransducers), attached to or fabricated on a substrate or solid surface,such as glass, plastic, silicon-chip, IC chip or other material formingan array. The arrays (such as sensor/transducer arrays) can be used tomeasure the signal locations and levels of large numbers, e.g., tens,thousands, millions, or billions of reactions or combinationssimultaneously. An array may also contain a small number of substances,e.g., a few or a dozen. The substances in the array can be identical ordifferent from each other. The array can assume a variety of formats,e.g., libraries of soluble molecules; libraries of compounds tethered toresin beads, silica chips, or other solid supports. The array couldeither be a macroarray or a microarray, depending on the size of thepads (features) on the array. A macroarray generally contains pad(feature) sizes of about 300 microns or as small as 1 micron, or even0.1 micron. A sensor array would generally contain pad sizes of lessthan 300 microns. Sensing elements (e.g., sensor array features orsensor pads) of the sensor/transducer array can be electronicallyindividually addressable.

The term “analyte” refers to a molecule of interest that is to bedetected and/or analyzed, e.g., a nucleotide, an oligonucleotide, apolynucleotide, a peptide, or a protein. The analyte, target or targetmolecule could be a small molecule, biomolecule, or nanomaterial such asbut not necessarily limited to a small molecule that is biologicallyactive, nucleic acids and their sequences, peptides and polypeptides, aswell as nanostructure materials chemically modified with biomolecules orsmall molecules capable of binding to molecular probes such aschemically modified carbon nanotubes, carbon nanotube bundles,nanowires, nanoclusters or nanoparticles. The target molecule may be afluorescently labeled antigen, antibody, DNA or RNA. A “bioanalyte”refers to an analyte that is a biomolecule. Specifically, analytes forDNA sequencing can be samples containing nucleic acid molecules, such asgenomic or synthetic, or biochemically amplified DNA or cDNA. “Analyte”molecule can be used interchangeably with “target” molecule.

The term “tag” is used to refer to a marker or indicator distinguishableby the observer but not necessarily by the system used to identify ananalyte or target. A tag may also achieve its effect by undergoing apre-designed detectable process. Tags are often used in biologicalassays to be conjugated with, or attached to, an otherwise difficult todetect substance. At the same time, tags usually do not change or affectthe underlining assay process. A tag used in biological assays include,but not limited to, a radio-active material, a magnetic material,quantum dot, an enzyme, a liposome-based label, a chromophore, afluorophore, a dye, a nanoparticle, a quantum dot or quantum well, acomposite-organic-inorganic nano-cluster, a colloidal metal particle, ora combination thereof. In one embodiment, a tag or a label is preferablya metal-organic complex that can be induced to generate electron currentupon light exposure.

FIG. 13 illustrates a computing device 1300 in accordance with oneimplementation of the invention. The computing device 1300 houses aboard 1302. The board 1302 may include a number of components, includingbut not limited to a processor 1304 and at least one communication chip1306. The processor 1304 is physically and electrically coupled to theboard 1302. In some implementations the at least one communication chip1306 is also physically and electrically coupled to the board 1302. Infurther implementations, the communication chip 1306 is part of theprocessor 1304.

Depending on its applications, computing device 1300 may include othercomponents that may or may not be physically and electrically coupled tothe board 1302. These other components include, but are not limited to,volatile memory (e.g., DRAM), non-volatile memory (e.g., ROM), flashmemory, a graphics processor, a digital signal processor, a cryptoprocessor, a chipset, an antenna, a display, a touchscreen display, atouchscreen controller, a battery, an audio codec, a video codec, apower amplifier, a global positioning system (GPS) device, a compass, anaccelerometer, a gyroscope, a speaker, a camera, and a mass storagedevice (such as hard disk drive, compact disk (CD), digital versatiledisk (DVD), and so forth).

The communication chip 1306 enables wireless communications for thetransfer of data to and from the computing device 1300. The term“wireless” and its derivatives may be used to describe circuits,devices, systems, methods, techniques, communications channels, etc.,that may communicate data through the use of modulated electromagneticradiation through a non-solid medium. The term does not imply that theassociated devices do not contain any wires, although in someembodiments they might not. The communication chip 1306 may implementany of a number of wireless standards or protocols, including but notlimited to Wi-Fi (IEEE 802.11 family), WiMAX (IEEE 802.16 family), IEEE802.20, long term evolution (LTE), Ev-DO, HSPA+, HSDPA+, HSUPA+, EDGE,GSM, GPRS, CDMA, TDMA, DECT, Bluetooth, derivatives thereof, as well asany other wireless protocols that are designated as 3G, 4G, 5G, andbeyond. The computing device 1300 may include a plurality ofcommunication chips 1306. For instance, a first communication chip 1306may be dedicated to shorter range wireless communications such as Wi-Fiand Bluetooth and a second communication chip 1306 may be dedicated tolonger range wireless communications such as GPS, EDGE, GPRS, CDMA,WiMAX, LTE, Ev-DO, and others.

The processor 1304 of the computing device 1300 includes an integratedcircuit die packaged within the processor 1304. In some implementationsof the invention, the integrated circuit die of the processor includesor is coupled to an integrated transducer array, in accordance withimplementations of the invention. The term “processor” may refer to anydevice or portion of a device that processes electronic data fromregisters and/or memory to transform that electronic data into otherelectronic data that may be stored in registers and/or memory.

The communication chip 1306 also includes an integrated circuit diepackaged within the communication chip 1306. In accordance with anotherimplementation of the invention, the integrated circuit die of thecommunication chip includes or is coupled with an integrated transducerarray in accordance with implementations of the invention.

In further implementations, another component housed within thecomputing device 1300 may contain an integrated circuit die thatincludes or is coupled with an integrated transducer array in accordancewith implementations of the invention.

In various implementations, the computing device 1300 may be a laptop, anetbook, a notebook, an ultrabook, a smartphone, a tablet, a personaldigital assistant (PDA), an ultra mobile PC, a mobile phone, a desktopcomputer, a server, a printer, a scanner, a monitor, a set-top box, anentertainment control unit, a digital camera, a portable music player,or a digital video recorder. In further implementations, the computingdevice 1300 may be any other electronic device that processes data.

Embodiments of the present invention may be provided as a computerprogram product, or software, that may include a machine-readable mediumhaving stored thereon instructions, which may be used to program acomputer system (or other electronic devices) to perform a processaccording to the present invention. A machine-readable medium includesany mechanism for storing or transmitting information in a form readableby a machine (e.g., a computer). For example, a machine-readable (e.g.,computer-readable) medium includes a machine (e.g., a computer) readablestorage medium (e.g., read only memory (“ROM”), random access memory(“RAM”), magnetic disk storage media, optical storage media, flashmemory devices, etc.), a machine (e.g., computer) readable transmissionmedium (electrical, optical, acoustical or other form of propagatedsignals (e.g., infrared signals, digital signals, etc.)), etc.

FIG. 14 illustrates a diagrammatic representation of a machine in theexemplary form of a computer system 1400 within which a set ofinstructions, for causing the machine to perform any one or more of themethodologies discussed herein, may be executed. In alternativeembodiments, the machine may be connected (e.g., networked) to othermachines in a Local Area Network (LAN), an intranet, an extranet, or theInternet. The machine may operate in the capacity of a server or aclient machine in a client-server network environment, or as a peermachine in a peer-to-peer (or distributed) network environment. Themachine may be a personal computer (PC), a tablet PC, a set-top box(STB), a Personal Digital Assistant (PDA), a cellular telephone, a webappliance, a server, a network router, switch or bridge, or any machinecapable of executing a set of instructions (sequential or otherwise)that specify actions to be taken by that machine. Further, while only asingle machine is illustrated, the term “machine” shall also be taken toinclude any collection of machines (e.g., computers) that individuallyor jointly execute a set (or multiple sets) of instructions to performany one or more of the methodologies discussed herein.

The exemplary computer system 1400 includes a processor 1402, a mainmemory 1404 (e.g., read-only memory (ROM), flash memory, dynamic randomaccess memory (DRAM) such as synchronous DRAM (SDRAM) or Rambus DRAM(RDRAM), etc.), a static memory 1406 (e.g., flash memory, static randomaccess memory (SRAM), etc.), and a secondary memory 1418 (e.g., a datastorage device), which communicate with each other via a bus 1430.

Processor 1402 represents one or more general-purpose processing devicessuch as a microprocessor, central processing unit, or the like. Moreparticularly, the processor 1402 may be a complex instruction setcomputing (CISC) microprocessor, reduced instruction set computing(RISC) microprocessor, very long instruction word (VLIW) microprocessor,processor implementing other instruction sets, or processorsimplementing a combination of instruction sets. Processor 1402 may alsobe one or more special-purpose processing devices such as an applicationspecific integrated circuit (ASIC), a field programmable gate array(FPGA), a digital signal processor (DSP), network processor, or thelike. Processor 1402 is configured to execute the processing logic 1426for performing the operations discussed herein.

The computer system 1400 may further include a network interface device1408. The computer system 1400 also may include a video display unit1410 (e.g., a liquid crystal display (LCD) or a cathode ray tube (CRT)),an alphanumeric input device 1412 (e.g., a keyboard), a cursor controldevice 1414 (e.g., a mouse), and a signal generation device 1416 (e.g.,a speaker).

The secondary memory 1418 may include a machine-accessible storagemedium (or more specifically a computer-readable storage medium) 1431 onwhich is stored one or more sets of instructions (e.g., software 1422)embodying any one or more of the methodologies or functions describedherein. The software 1422 may also reside, completely or at leastpartially, within the main memory 1404 and/or within the processor 1402during execution thereof by the computer system 1400, the main memory1404 and the processor 1402 also constituting machine-readable storagemedia. The software 1422 may further be transmitted or received over anetwork 1420 via the network interface device 1408.

While the machine-accessible storage medium 1431 is shown in anexemplary embodiment to be a single medium, the term “machine-readablestorage medium” should be taken to include a single medium or multiplemedia (e.g., a centralized or distributed database, and/or associatedcaches and servers) that store the one or more sets of instructions. Theterm “machine-readable storage medium” shall also be taken to includeany medium that is capable of storing or encoding a set of instructionsfor execution by the machine and that cause the machine to perform anyone or more of the methodologies of the present invention. The term“machine-readable storage medium” shall accordingly be taken to include,but not be limited to, solid-state memories, and optical and magneticmedia.

Thus, embodiments of the present invention include highly selectivecoated-electrode nanogap transducers for the detection of redoxmolecules.

In an embodiment, an analyte detection system includes one or moretransducer electrodes having a surface for analyte detection. Thesurface includes a coating to inhibit direct contact of analyte with thesurface of the one or more transducer electrodes.

In one embodiment, the coating is composed of a dielectric film.

In one embodiment, the dielectric film is composed of a material suchas, but not limited to, Ta₂O₅, TiO₂, SiO₂, Y₂O₃, Al₂O₃, HfO₂, ZrO₂,ZrSiO₄, BaTiO₃, BaZrO₃ or Si₃N₄.

In one embodiment, the dielectric film has a thickness approximately inthe range of 0-7 nanometers.

In one embodiment, the dielectric film has a low energy barrier toenable electron tunneling or hopping through or over the energy barrierto maintain a similar electron transfer rate relative to a bareelectrode.

In one embodiment, the coating is composed of a thin conductive materialthat is non-catalytic and non-electrochemically active.

In one embodiment, the thin conductive material is ruthenium (Ru).

In one embodiment, the coating is composed of an organic film.

In one embodiment, the organic film is composed of a well-defined orself-assembled monolayer or very thin multiple layers of hydrophilic andbiocompatible organic compounds such as, but not limited to,polyethylene glycols, anilines, phosphonates, thiols or peptides.

In one embodiment, the organic film is composed of a tetra-DTT phosphateor a tetra-DTT-ferrocene phosphate.

In one embodiment, the organic film has a low energy barrier to enableelectron tunneling or hopping through or over the energy barrier tomaintain a similar electron transfer rate relative to a bare electrode.

In one embodiment, the one or more transducer electrodes is composed ofa material such as, but not limited to, platinum, diamond, gold, indiumtin oxide (ITO) or iridium oxide.

In one embodiment, the coating reduces or prevents catalytic reaction ofthe one or more transducer electrodes with solution additives andreduces the effect of adsorbed species without affecting the electrontransfer at reducing and oxidizing electrodes.

In one embodiment, the one or more transducer electrodes are included ina dual-electrode nanogap chemical and biochemical sensor based ondetection of a redox-active molecule using redox cycling.

In one embodiment, the analyte detection system includes only onetransducer electrode are included in a single-electrode based onchemical cycling.

In an embodiment, a method of fabricating a dual-electrode nanogapchemical and biochemical sensor involves forming a bottom electrodeabove a substrate. The method also involves forming a first coating onthe bottom electrode. The method also involves forming a sacrificiallayer on the first coating. The method also involves forming a secondcoating on the sacrificial layer. The method also involves forming a topelectrode on the second coating. The method also involves, subsequent toforming the second coating and the top electrode, removing thesacrificial layer without removing the first and second coatings.

In one embodiment, forming the first and second coatings involvesforming a dielectric film.

In one embodiment, forming the dielectric film involves forming amaterial such as, but not limited to, Ta₂O₅, TiO₂, SiO₂, Y₂O₃, Al₂O₃,HfO₂, ZrO₂, ZrSiO₄, BaTiO₃, BaZrO₃ or Si₃N₄.

In one embodiment, forming the first and second coatings involvesforming a thin conductive material that is non-catalytic andnon-electrochemically active.

In one embodiment, forming the thin conductive material involves forminga ruthenium (Ru) layer.

In an embodiment, a method of fabricating an analyte detection systeminvolves forming one or more bare transducer electrodes having a surfacefor analyte detection. The method also involves forming an organic filmon the surface to inhibit direct contact of analyte with the surface ofthe one or more transducer electrodes.

In one embodiment, forming the organic film involves forming awell-defined or self-assembled monolayer or very thin multiple layers ofhydrophilic and biocompatible organic compounds such as, but not limitedto, polyethylene glycols, anilines, phosphonates, thiols or peptides.

In one embodiment, forming the organic film involves forming a film of atetra-DTT phosphate or of a tetra-DTT-ferrocene phosphate.

What is claimed is:
 1. An analyte detection apparatus, comprising: oneor more transducer electrodes having a surface for analyte detection,the surface comprising a coating to inhibit direct contact of analytewith the surface of the one or more transducer electrodes, wherein thecoating comprises an organic film comprising a tetra-DTT phosphate or atetra-DTT-ferrocene phosphate.
 2. The analyte detection apparatus ofclaim 1, wherein the organic film has a low energy barrier to enableelectron tunneling or hopping through or over the energy barrier tomaintain a similar electron transfer rate relative to a bare electrode.3. The analyte detection apparatus of claim 1, wherein the one or moretransducer electrodes comprises a material selected from the groupconsisting of platinum, diamond, gold, indium tin oxide (ITO) andiridium oxide.
 4. The analyte detection apparatus of claim 1, whereinthe coating reduces or prevents catalytic reaction of the one or moretransducer electrodes with solution additives and reduces the effect ofadsorbed species without significantly affecting the electron transferat reducing and oxidizing electrodes.
 5. The analyte detection apparatusof claim 1, wherein the one or more transducer electrodes are includedin a dual-electrode nanogap chemical and biochemical sensor based ondetection of a redox-active molecule using redox cycling.
 6. The analytedetection apparatus of claim 1, wherein the analyte detection systemincludes only one transducer electrode included in a single-electrodebased on chemical cycling.